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Kågedal, Katarina
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Publications (10 of 42) Show all publications
Boman, A., Svensson, S., Boxer, A., Rojas, J. C., Seeley, W. W., Karydas, A., . . . Svenningsson, P. (2016). Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid. Journal of Parkinson's Disease, 6(2), 307-315
Open this publication in new window or tab >>Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
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2016 (English)In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 6, no 2, p. 307-315Article in journal (Refereed) Published
Abstract [en]

Introduction: Clinical diagnosis of parkinsonian syndromes like Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy is hampered by overlapping symptomatology and lack of biomarkers for diagnosis, and definitive diagnosis is only possible post-mortem. Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that levels and profiles of lysosomal network proteins in cerebrospinal fluid could be changed in these parkinsonian syndromes.

Methods: Cerebrospinal fluid samples were collected from Parkinson’s disease patients (n=18), clinically diagnosed 4-repeat tauopathy patients, corticobasal syndrome (n=6) and progressive supranuclear palsy (n=5), pathologically diagnosed progressive supranuclear palsy (n=8) and corticobasal degeneration patients (n=7). Each patient set was compared to its appropriate control group consisting of the same number of age and gender matched individuals. Lysosomal network protein levels were detected via Western blotting.

Results: Lysosomal network proteins have markedly different cerebrospinal fluid protein levels and profiles in Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in Parkinson´s disease; early endosomal antigen 1 was decreased and lysozyme increased in progressive supranuclear palsy; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in corticobasal degeneration.

Conclusions: Lysosomal network proteins hold promise of being interesting novel candidates for biomarker studies and for elucidating disease mechanisms of Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy, but further validation studies will be needed to assess the specificity and the predictive value of these proteins in CSF.

Place, publisher, year, edition, pages
IOS Press, 2016
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122342 (URN)10.3233/JPD-150759 (DOI)000378352200004 ()
Note

Funding agencies:This work was supported by the Swedish Alzheimer foundation, the Swedish Dementia foundation, Linkoping University Neurobiology Center, Karin & Sten CBD Solutions AB, AZ-KI TSC, ALF, US National Institutes of Health R01AG038791 and U54NS092089, the Tau Consortium, the Hellman Family Foundation.

Vid tiden för disputationen förelåg publikationen endast som manuskript

Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
Klionsky, D. J., Boman, A., Kågedal, K., Kurz, T., Mohseni, S., Öllinger, K. & Zughaier, S. M. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 2(1), 1-222
Open this publication in new window or tab >>Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
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2016 (English)In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 2, no 1, p. 1-222Article, review/survey (Refereed) Published
Place, publisher, year, edition, pages
Taylor & Francis, 2016
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-137050 (URN)10.1080/15548627.2015.1100356 (DOI)000373595400001 ()26799652 (PubMedID)
Note

The article contains 2467 authors of which five are affiliated with LiU and have the following author order:

Author no. 177: Andrea Boman

Author no. 968: Katarina Kågedal

Author no. 1106: Tino Kurz

Author no. 1449: Simin Mohseni

Author no. 1559: Karin Öllinger

Available from: 2017-05-02 Created: 2017-05-02 Last updated: 2019-03-14Bibliographically approved
Civitelli, L., Sandin, L., Nelson, E., Iqbal Khattak, S., Brorsson, A.-C. & Kågedal, K. (2016). The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties. Journal of Biological Chemistry, 291(17), 9233-9243
Open this publication in new window or tab >>The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties
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2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 17, p. 9233-9243Article in journal (Refereed) Published
Abstract [en]

Aggregation of the amyloid-(beta) peptide (A beta) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the A beta peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the A beta fibrillation pathway may be a valid approach to reduce A beta cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic A beta species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting A beta-mediated cytotoxicity. Moreover, p-FTAA bound to early formed A beta species and induced a rapid formation of beta-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable A beta species that were nontoxic which indicates that p-FTAA might have therapeutic potential.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2016
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-128747 (URN)10.1074/jbc.M115.696229 (DOI)000374849000033 ()26907684 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Torsten Soderberg Foundation; Alzheimer Foundation; Dementia Foundation; Linkoping University Neurobiology Center

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2018-03-20
Helmfors, L., Boman, A., Civitelli, L., Nath, S., Sandin, L., Janefjord, C., . . . Kågedal, K. (2015). Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease. Neurobiology of Disease, 83, 122-133
Open this publication in new window or tab >>Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
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2015 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, p. 122-133Article in journal (Refereed) Published
Abstract [en]

The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Lysozyme, Biomarker, Alzheimer disease, Drosophila, Aβ aggregation
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122341 (URN)10.1016/j.nbd.2015.08.024 (DOI)000366230000012 ()26334479 (PubMedID)
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
Boman, A., Janefjord, C., Halliday, G., Zetterberg, H., Blennow, K., Garner, B., . . . Kågedal, K. (2015). The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease.
Open this publication in new window or tab >>The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease
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2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Dysfunction in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are implicated in the pathways in Alzheimer’s disease brain pathology. This dysfunction is mirrored in the cerebrospinal fluid where a specific subset of lysosomal network proteins are found at elevated levels, lysosomal associated membrane protein-2 (LAMP-2) being one of the identified lysosomal proteins. Here we report that hippocampus and frontal cortex in Alzheimer’s disease cases have increased mRNA and protein expression of LAMP-2, and thus these brain areas are likely involved in the increased LAMP-2 levels seen in cerebrospinal fluid from Alzheimer’s disease patients. The increased LAMP-2 levels correlated with increased levels of β-amyloid1-42 (Aβ1-42). Oligomeric Aβ1-42 caused an upregulation of intracellular LAMP-2 in neuroblastoma cells, but did not trigger the release of LAMP-2 to the extracellular milieu, indicating that other cell types or mechanisms are responsible for the LAMP-2 release seen in cerebrospinal fluid. Overexpression of LAMP-2 in neuroblastoma cells caused a trend of reduction of secreted Aβ1-42 and changed the processing pattern of the Aβ precursor protein. These results indicate that Aβ1-42 mediated increase of LAMP-2 expression can act as a regulator of Aβ generation and secretion. LAMP-2 overexpression did not change the cellular uptake of extracellularly added Aβ1-42, but caused a delayed clearance of Aβ1-42. Whether the prolonged intracellular localization of Aβ1-42 in LAMP-2 overexpressing cells can change the transmission or degradation of Aβ remains to be investigated.

Keywords
AβPP processing, Alzheimer’s disease, β-amyloid, autophagy, LAMP-2, lysosome
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122345 (URN)
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
Englund, U., Gertow, J., Kågedal, K. & Elinder, F. (2014). A Voltage Dependent Non-Inactivating Na+ Channel Activated during Apoptosis in Xenopus Oocytes. PLoS ONE, 9(2), 0088381
Open this publication in new window or tab >>A Voltage Dependent Non-Inactivating Na+ Channel Activated during Apoptosis in Xenopus Oocytes
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. 0088381-Article in journal (Refereed) Published
Abstract [en]

Ion channels in the plasma membrane are important for the apoptotic process. Different types of voltage-gated ion channels are up-regulated early in the apoptotic process and block of these channels prevents or delays apoptosis. In the present investigation we examined whether ion channels are up-regulated in oocytes from the frog Xenopus laevis during apoptosis. The two-electrode voltage-clamp technique was used to record endogenous ion currents in the oocytes. During staurosporine-induced apoptosis a voltage-dependent Na+ current increased three-fold. This current was activated at voltages more positive than 0 mV (midpoint of the open-probability curve was +55 mV) and showed almost no sign of inactivation during a 1-s pulse. The current was resistant to the Na+-channel blockers tetrodotoxin (1 mM) and amiloride (10 mM), while the Ca2+-channel blocker verapamil (50 mM) in the bath solution completely blocked the current. The intracellular Na+ concentration increased in staurosporine-treated oocytes, but could be prevented by replacing extracellular Na+ whith either K+ or Choline(+). Prevention of this influx of Na+ also prevented the STS-induced up-regulation of the caspase-3 activity, suggesting that the intracellular Na+ increase is required to induce apoptosis. Taken together, we have found that a voltage dependent Na+ channel is up-regulated during apoptosis and that influx of Na+ is a crucial step in the apoptotic process in Xenopus oocytes.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105899 (URN)10.1371/journal.pone.0088381 (DOI)000332396200017 ()
Available from: 2014-04-14 Created: 2014-04-12 Last updated: 2018-01-25
Kim, W. S., Kågedal, K. & Halliday, G. M. (2014). Alpha-synuclein biology in Lewy body diseases.. Alzheimer's research & therapy, 6(5), Article ID 73.
Open this publication in new window or tab >>Alpha-synuclein biology in Lewy body diseases.
2014 (English)In: Alzheimer's research & therapy, ISSN 1758-9193, Vol. 6, no 5, article id 73Article in journal (Refereed) Published
Abstract [en]

α-Synuclein is an abundantly expressed neuronal protein that is at the center of focus in understanding a group of neurodegenerative disorders called α-synucleinopathies, which are characterized by the presence of aggregated α-synuclein intracellularly. Primary α-synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, with α-synuclein also found secondarily in a number of other diseases, including Alzheimer's disease. Understanding how α-synuclein aggregates form in these different disorders is important for the understanding of its pathogenesis in Lewy body diseases. PD is the most prevalent of the α-synucleinopathies and much of the initial research on α-synuclein Lewy body pathology was based on PD but is also relevant to Lewy bodies in other diseases (dementia with Lewy bodies and Alzheimer's disease). Polymorphism and mutation studies of SNCA, the gene that encodes α-synuclein, provide much evidence for a causal link between α-synuclein and PD. Among the primary α-synucleinopathies, multiple system atrophy is unique in that α-synuclein deposition occurs in oligodendrocytes rather than neurons. It is unclear whether α-synuclein originates from oligodendrocytes or whether it is transmitted somehow from neurons. α-Synuclein exists as a natively unfolded monomer in the cytosol, but in the presence of lipid membranes it is thought to undergo a conformational change to a folded α-helical secondary structure that is prone to forming dimers and oligomers. Posttranslational modification of α-synuclein, such as phosphorylation, ubiquitination and nitration, has been widely implicated in α-synuclein aggregation process and neurotoxicity. Recent studies using animal and cell models, as well as autopsy studies of patients with neuron transplants, provided compelling evidence for prion-like propagation of α-synuclein. This observation has implications for therapeutic strategies, and much recent effort is focused on developing antibodies that target extracellular α-synuclein.

Place, publisher, year, edition, pages
BioMed Central, 2014
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-115278 (URN)10.1186/s13195-014-0073-2 (DOI)000343200300017 ()25580161 (PubMedID)
Available from: 2015-03-12 Created: 2015-03-12 Last updated: 2017-02-20Bibliographically approved
Armstrong, A., Mattsson, N., Appelqvist, H., Janefjord, C., Sandin, L., Agholme, L., . . . Kågedal, K. (2014). Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease. Neuromolecular medicine, 16(1), 150-160
Open this publication in new window or tab >>Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
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2014 (English)In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 16, no 1, p. 150-160Article in journal (Refereed) Published
Abstract [en]

The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.

Place, publisher, year, edition, pages
Humana Press, 2014
Keywords
PICALM; DRAM; TFEB; Cathepsins; Proteasome; hsc70
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-105235 (URN)10.1007/s12017-013-8269-3 (DOI)000331101900015 ()
Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2018-01-11
Agholme, L., Nath, S., Domert, J., Marcusson, J., Kågedal, K. & Hallbeck, M. (2014). Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease. Molecular and Cellular Neuroscience, 58, 29-39
Open this publication in new window or tab >>Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
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2014 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 58, p. 29-39Article in journal (Refereed) Published
Abstract [en]

Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

Place, publisher, year, edition, pages
Elsevier, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-81339 (URN)10.1016/j.mcn.2013.11.001 (DOI)000331853600004 ()
Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2017-12-07Bibliographically approved
Appelqvist, H., Wäster, P., Kågedal, K. & Öllinger, K. (2013). The lysosome: from waste bag to potential therapeutic target. Journal of Molecular Cell Biology, 5(4), 214-226
Open this publication in new window or tab >>The lysosome: from waste bag to potential therapeutic target
2013 (English)In: Journal of Molecular Cell Biology, ISSN 1674-2788, E-ISSN 1759-4685, Vol. 5, no 4, p. 214-226Article, review/survey (Refereed) Published
Abstract [en]

Lysosomes are ubiquitous membrane-bound intracellular organelles with an acidic interior. They are central for degradation and recycling of macromolecules delivered by endocytosis, phagocytosis, and autophagy. In contrast to the rather simplified view of lysosomes as waste bags, nowadays lysosomes are recognized as advanced organelles involved in many cellular processes and are considered crucial regulators of cell homeostasis. The function of lysosomes is critically dependent on soluble lysosomal hydrolases (e.g. cathepsins) as well as lysosomal membrane proteins (e.g. lysosome-associated membrane proteins). This review focuses on lysosomal involvement in digestion of intra- and extracellular material, plasma membrane repair, cholesterol homeostasis, and cell death. Regulation of lysosomal biogenesis and function via the transcription factor EB (TFEB) will also be discussed. In addition, lysosomal contribution to diseases, including lysosomal storage disorders, neurodegenerative disorders, cancer, and cardiovascular diseases, is presented.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy B - Oxford Open Option D, 2013
Keywords
degradation, apoptosis, lysosomal membrane permeabilization, exocytosis, cholesterol
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97246 (URN)10.1093/jmcb/mjt022 (DOI)000322914000002 ()
Note

Funding Agencies|Swedish Research Council||Swedish Cancer Society||Signhild Engkvist foundation||

Available from: 2013-09-05 Created: 2013-09-05 Last updated: 2017-12-06
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